Unmasked Acyl Anion Equivalent from Acid Chloride with Indium

Letter pubs.acs.org/OrgLett

Unmasked Acyl Anion Equivalent from Acid Chloride with Indium: Reversed-Polarity Synthesis of Unsymmetric Aryl Aryl and Alkenyl Aryl Ketone through Palladium-Catalyzed Cross-Coupling Reaction† Dohyung Lee, Taekyu Ryu, Youngchul Park, and Phil Ho Lee* Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea S Supporting Information *

ABSTRACT: A reversed-polarity synthetic method of a range of unsymmetric aryl aryl and alkenyl aryl ketones has been developed through Pd-catalyzed cross-coupling reaction of acylindium reagents generated in situ from easily available acid chlorides and indium with various electrophiles such as aryl iodide and triflate and alkenyl triflate.

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nanes, -zirconocenes, and -silanes have been generally used as acyl anion equivalents (Scheme 2). Although acylstannanes and

ransition-metal-catalyzed cross-coupling reaction of a number of electrophilic coupling partners with organometallic reagents is one of the most straightforward methods for C−C bond formation.1 To date, Pd catalysis has been applied widely in the synthesis of a variety of ketones constituting aryl aryl, alkyl aryl, and alkyl alkyl groups. Synthetic strategies of ketones through Pd catalysis could be generally classified into three categories: substitution and cross-coupling reaction of electrophilic acid derivatives with organometallic reagents (eq 1),2 carbonylative cross-coupling reaction of aryl halides with organometallic reagents under CO atmosphere (eq 2),3 and cross-coupling reaction of acyl anion equivalents with electrophiles (eq 3) (Scheme 1).

Scheme 2. Synthesis of Ketones Using Cross-Coupling Reaction of Acyl Organometallic Reagents

Scheme 1. Synthetic Methods for Ketone Synthesis -zirconocenes were reacted with aryl halide to afford one example each of ketone in low yield,4 acylsilanes in reaction with a range of aryl bromides gave diaryl ketones in variable yields (eq 4).5 These reagents were reacted with allylic halides and esters to afford β,γ-unsaturated ketones (eq 5).4,6 Acylstannane and -zirconocene reagents produced unsymmetric 1,2-diketones in reaction with acid chlorides (eq 6).4,7 Aldehydes, imines, or hydrazones were also arylated with aryl iodides and tins or potassium aryl(trifluoro)borates through Pd catalysis.8 Pd-catalyzed arylation of electron-rich olefins by aryl halides followed by acidic hydrolysis was reported in the formation of diaryl ketones.9 However, these methods require additional and tedious synthetic steps under harsh conditions for the preparation of the unmasked acyl anion equivalents. Also, we are not aware of

The first two methods have been commonly used in the formation of ketones. However, the last one has been limited in application due to difficult preparation of acyl anion equivalents. Although acyl anion equivalents in cross-coupling reaction have been used with some limitations, the use of acyl organometallic reagents provides an effective method for the polarity-reversed synthesis of ketones. Up to now, acylstan© 2014 American Chemical Society

Received: January 1, 2014 Published: February 7, 2014 1144

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Among the solvents (THF, DMF, DMSO, NMP, THF−NMP, TH−DMF, and TH−DMSO) tested, NMP gave the best result (see the Supporting Information). The best result was obtained from the reaction of 2a with acylindium reagent, which was generated in situ from 1a (1.5 equiv) and indium (3 equiv) with lithium chloride (3 equiv), TMSCl (6 mol %), and 1,2dibromoethane (15 mol %) at 40 °C for 3 h, in the presence of Pd2(dba)3 (2 mol %) in NMP at room temperature after 3 h, producing 3a in 86% yield (entry 4). The use of a wide array of ligands [Xantphos, DPEphos, Ph3P, Cy3P, Cy2(Biphenyl)P, (furyl)3P, and (o-tolyl)3P] did not increase the yield (see the Supporting Information). Other palladium catalysts such as Pd(OAc)2 , Pd(Ph 3 P) 2 Cl 2 , and Pd(Ph 3 P) 4 were totally ineffective (entries 5, 6, and 8). A number of additives such as LiBr, LiI, KBr, and KI failed to give the coupling product in good yield (see the Supporting Information). Control experiments in the reaction of 4-iodoacetophenone with benzoyl chloride and indium suggest that use of TMSCl as well as dibromoethane is essential for giving successful results (see the Supporting Information). Commercially available indium does not react with benzoyl chloride. However, when LiCl was added to indium powder that had been activated with 1,2dibromoethane and TMSCl, an efficient insertion occurred.10−12 Ethyl 4-iodobenzoate pretreated with indium, lithium chloride, TMSCl, and dibromoethane in NMP was reacted with benzoyl chloride in the presence of Pd2(dba)3 to produce 3a (12%) and 4 (52%), indicating that 4ethoxycarbonylphenylindium was not involved in this reaction.11 Because benzoyltrimethylsilane was not detected in the treatment of 1a with In, LiCl, and TMSCl, the coupling reaction via the formation of benzoyltrimethylsilane ruled out.5 Next, we applied this catalytic system to various electrophiles to demonstrate the efficiency and scope of the present method (Scheme 4). Phenyl iodide was reacted with acylindium to produce benzophenone 3b in 78% yield. The presence of an electron-donating group on the phenyl ring lowered the product yield. 3- and 4-Iodotoluene were converted to the corresponding ketones 3c and 3d in 58% and 47% yields, respectively, under modified conditions [4 mol % of (Ph3P)4Pd, 60 °C]. However, 3- and 4-iodobenzotrifluoride having an electron-withdrawing trifluoromethyl group gave the corresponding 3- and 4-trifluoromethylphenyl phenyl ketones 3e (71%) and 3f (63%). When 3-iodobenzaldehyde having an electrophilic labile formyl group was subjected to the standard conditions, the desired product 3g was obtained in 77% yield. Treatment of 3- and 4-iodoacetophenone with acylindium reagent also provided the desired ketones 3h and 3i in 71% and 78% yields, respectively. Aryl iodide having an ethoxycarbonyl group furnished the desired ketone 3j in 88% yield. 4Iodobenzonitrile was reacted with acylindium, affording 4cyanophenyl phenyl ketone 3k in 67% yield. The tolerance of the formyl, ketone, ester, and nitrile group is especially significant, as successive functional group transformations are hopeful. As an extension of this work, we applied this catalytic system in aryl and alkenyl triflate. The reactivity of aryl triflate derived from ethyl 4-hydroxybenzoate is similar to that of ethyl 4-iodobenzoate, providing 3a in 81% yield in the presence of 4 mol % of Pd2(dba)3. Subjecting alkenyl triflate to generated in situ acylindium produced the corresponding alkenyl aryl ketone 3l in 67% yield. Encouraged by these results, we investigated the coupling reaction of acyl anion equivalents having useful functional groups with a variety of aryl iodides 2 (Scheme 5). Acylindium

any reported synthetic examples of acyl anion equivalent generated in situ from easily available acid chloride. In our continuing efforts to develop Pd-catalyzed cross-coupling reactions using organoindium reagents,10 we have been interested in development of a novel synthetic route to acyl anion equivalents using indium and then envisioned a crosscoupling reaction of electrophilic coupling partners with acyl anion equivalents generated in situ from indium and acid halides. Herein, we report the challenging reversed-polarity synthetic method of a diversity of ketones via Pd-catalyzed cross-coupling reaction of acylindium reagents generated in situ from easily accessible acid chlorides and indium at room temperature (Scheme 3). Scheme 3. Reversed-Polarity Synthesis of Ketones via CrossCoupling Reaction with Acylindium Reagents

To access unmasked acyl anion equivalents from acid chlorides, we studied the reactions of ethyl 4-iodobenzoate (2a) with organoindium reagents generated in situ from benzoyl chloride (1a) and indium in the presence of palladium catalyst and additive (Table 1). After 1a was treated with Table 1. Reaction Optimization of Reversed-Polarity Ketone Synthesisa

entry

cat.

solvent

temp (°C)

time (h)

yieldb (%)

1 2 3 4 5 6 7 8

Pd2 (dba)3 Pd2 (dba)3 Pd2 (dba)3 Pd2 (dba)3 Pd (OAc)2 Pd (Ph3P)2Cl2 Pd2 (dba)3CHCl3 Pd (Ph3P)4

DMF DMSO NMP NMP NMP NMP NMP NMP

90 90 60 25 60 60 60 60

2 12 5 3 12 12 12 12

31 (27) 0 77 (11) 86 0 0 48 (15) 0

a 1a (1.5 equiv) and 2a (1 equiv) were used in the presence of In (3 equiv), LiCl (3 equiv), TMSCl (6 mol %), and (BrCH2)2 (15 mol %) in NMP. Indium reagent was prepared at 50 °C (entries 1−3) and 40 °C (entries 4−8) for 3 h. In the case of Pd(OAc)2 and Pd(Ph3P)4, 4 mol % of catalyst was used. bNumbers in parentheses is isolated yield of 4,4′-diethoxycarbonyl-1,1′-biphenyl (4).

indium in the presence of LiCl, TMSCl, and 1,2-dibromoethane in DMF (50 °C, 3 h), the reaction mixture was subjected to 2a in the presence of Pd2(dba)3, producing ethyl 4-benzoyl benzoate 3a in 31% yield together with 4,4′diethoxycarbonyl-1,1′-biphenyl (27%, 4) (entry 1). However, the reaction did not proceed in DMSO (entry 2). Surprisingly, NMP as a solvent increased yield of 3a to 77% (entry 3). Therefore, the formation of acyl anion equivalent was assumed. 1145

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reagent generated in situ from 3-methylbenzoyl chloride 1b and indium under the standard conditions was reacted with 3iodobenzotrifluororide, 3-iodoacetophenone, ethyl 4-iodobenzoate, and 3-iodobenzonitrile to produce the corresponding unsymmetric aryl aryl ketones 3m, 3n, 3o, and 3p in good yields. Reaction of 4-tert-butylbenzoyl chloride 1c with indium delivered also an acyl anion equivalent that coupled with aryl iodides having labile acetyl, ethoxycarbonyl, and nitrile group to provide the desired unsymmetric ketones 3q, 3r, and 3s. Acylindium reagent derived from 4-methoxybenzoyl chloride 1d worked equally well with electron-deficient aryl iodide. However, preparation of acylindium reagent from 4-chlorobenzoyl chloride 1e and indium is not effective. To prove the mechanism of the present reaction, we conducted the reaction of acylindium reagent generated in situ from benzoyl chloride with 4-iodoacetophenone under the standard conditions in the presence of radical inhibitor. As expected, adding 2,2,6,6-tetramethylpiperidine-1-oxy (TEMPO) did not retard or suppress the reaction (eq 7). These results indicate that the present reaction does not seem to proceed through a radical process promoted by indium.13

Scheme 4. Preparation of Ketones from Coupling of Acylindium with Electrophilesa

a 1a (1.5 equiv) and 2 (1 equiv) were used in the presence of In (3 equiv), LiCl (3 equiv), TMSCl (6 mol %), (BrCH2)2 (15 mol %), and Pd2(dba)3 (2 mol %) in NMP unless otherwise noted. b4 mol % of (Ph3P)4Pd was used. Coupling was carried out at 60 °C. cCoupling was carried out at 10 °C. dTriflate was used. 4 mol % of Pd2(dba)3 was used.

To prove the anion character of acylindium reagent generated in situ from benzoyl chloride and indium, the prepared reagent was quenched with 10% HCl and 10% DCl to afford benzaldehyde (70%) and benzaldehyde-d1 (60%), respectively (eq 8). These results indicate that a variety of

Scheme 5. Preparation of Unsymmetric Aryl Aryl Ketones from Coupling of Acylindiuma

organoindium reagents obtained from the present reactions have anion character, and the possibility of a radical intermediate rules out the mechanism. The elucidation of the detailed reaction mechanism must wait further study. In conclusion, we have developed a reversed-polarity synthetic method for a diversity of unsymmetric aryl aryl and aryl alkenyl ketones via Pd-catalyzed cross-coupling reaction of acylindium reagents generated in situ from acid chlorides and indium. Because the direct synthetic method of unmasked acyl anion equivalents from easily available acid chlorides with indium has been developed for the first time under mild conditions, the present reaction is highly useful and promising. The tolerance of formyl, ketone, ester, and nitrile groups is especially practical, providing an opportunity for further functionalization.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures, characterization data, and copies of NMR spectra for all products. This material is available free of charge via the Internet at http://pubs.acs.org.

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a

1 (1.5 equiv) and 2 (1 equiv) were used in the presence of In (3 equiv), LiCl (3 equiv), TMSCl (6 mol %), (BrCH2)2 (15 mol %), and Pd2(dba)3 (2 mol %) in NMP unless otherwise noted.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 1146

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Notes

X.-G.; Li, J.-H. Org. Lett. 2011, 13, 2184. (l) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc. 2004, 126, 15356. (9) (a) Katz, J. D.; Lapointe, B. T.; Dinsmore, C. J. J. Org. Chem. 2009, 74, 8866. (b) Arvela, R. K.; Pasquini, S.; Larhed, M. J. Org. Chem. 2007, 72, 6390. (c) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751. (d) Xu, L.; Chen, W.; Xiao, J. J. Mol. Catal. A: Chem. 2002, 187, 189. (10) (a) Lee, P. H.; Sung, S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201. (b) Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265. (c) Seomoon, D.; Lee, K.; Kim, H.; Lee, P. H. Chem.Eur. J. 2007, 13, 5197. (d) Seomoon, D.; Lee, P. H. J. Org. Chem. 2008, 73, 1165. (e) Lee, K.; Seomoon, D.; Lee, P. H. Angew. Chem., Int. Ed. 2002, 41, 3901. (f) Kim, H.; Lee, K.; Kim, S.; Lee, P. H. Chem. Commun. 2010, 46, 6341. (g) Lee, P. H.; Mo, J.; Kang, D.; Eom, D.; Park, C.; Lee, C.H.; Jung, Y. M.; Hwang, H. J. Org. Chem. 2011, 76, 312. (h) Kim, S.; Seomoon, D.; Lee, P. H. Chem. Commun. 2009, 1873. (i) Mo, J.; Kim, S. H.; Lee, P. H. Org. Lett. 2010, 12, 424. (j) Lee, P. H.; Kim, S.; Lee, K.; Seomoon, D.; Kim, H.; Lee, S.; Kim, M.; Han, M.; Noh, K.; Livinghouse, T. Org. Lett. 2004, 6, 4825. (11) (a) Chen, Y.-H.; Sun, M.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 2236. (b) Chen, Y.-H.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 7648. (12) (a) Lee, J.-Y.; Lee, P. H. Bull. Korean Chem. Soc. 2007, 28, 1929. (b) Auge, J.; Lubin-Germain, N.; Thiaw-Woaye, A. Tetrahedron Lett. 1999, 40, 9245. (c) Auge, J.; Lubin-Germain, N.; Marque, S.; Seghrouchni, L. J. Organomet. Chem. 2003, 679, 79. (13) (a) Kim, J.-G.; Jang, D.-O. Bull. Korean Chem. Soc. 2009, 30, 27. (b) Marin, G.; Braga, A. L.; Rosa, A. S.; Galetto, F. Z.; Burrow, R. A.; Gallardo, H.; Paixão, M. W. Tetrahedron 2009, 65, 4614.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2011-0018355).

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DEDICATION

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REFERENCES

†

This paper is dedicated to Professor T. Livinghouse (Montana State University) on the occasion of his 60th birthday.

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